Keywords

Definitions and Assessing Severity

Severe ulcerative colitis (UC) was first defined by Truelove and Witts in 1955 using six simple criteria without any requirement for a sigmoidoscopic examination—six or more stools per day with one of the following: large amounts of blood, fever >37.8 °C, tachycardia >90, ESR > 30 mm/h, and hemoglobin <10.5 g/dl. These criteria are easily measured and have stood the test of time over half a century [1]. The Mayo Clinic Index (with slight variations also known as the Sutherland Index or the UC Disease Activity Index) has become a frequently used scoring index in clinical trials and includes sigmoidoscopic appearance and the physician’s global assessment. Another score known as the Modified Truelove-Witts Scoring Index, or the Lichtiger score, has been used most frequently in patients with intravenous (IV) corticosteroid-refractory UC. The Lichtiger score includes assessments for nocturnal bowel movements, incontinence, abdominal pain, cramping and tenderness, and the overall sense of “well-being.” While all of these scores list the salient features defining disease activity, the term “severe ulcerative colitis” as used in this chapter will refer to those patients with ongoing frequent bloody diarrhea with systemic signs and/or symptoms that significantly limit the patient’s quality of life and who fail to improve with maximal outpatient therapies and require hospitalization for further management.

Toxic megacolon refers to patients with dilation of the colon of >6 cm diameter associated with severe systemic toxicity. It is important to recognize that patients may present with toxicity without colonic dilation and are still at graver risk than patients with severe colitis without toxicity. Fulminant colitis is defined as any colitis that, in addition to the features of severe colitis, becomes rapidly worse, usually manifesting as severe abdominal pain and continuous bleeding requiring multiple transfusions. Medical therapy is inappropriate in fulminant colitis, and colectomy is the only suitable treatment.

Management: Investigations and Monitoring

The immediate goals of therapy are to reduce the signs and symptoms of the severe acute attack, allow the taper of corticosteroids, and initiate a strategy to achieve a long-term corticosteroid-free remission. The primary goal is not the avoidance of surgery. This is important to emphasize that the mortality from severe UC reduced dramatically from 24 to 7 % with the introduction of IV corticosteroids in the 1960s. Now the mortality in most units should be <1 %, and this reduction over the last 50 years is almost exclusively due to timely and expert surgical input. Close collaboration with a surgeon is therefore essential.

A sigmoidoscopy is done to assess disease severity and obtain biopsies to exclude a superimposed etiology, e.g., infection with Clostridium difficile (C. difficile) and cytomegalovirus (CMV). A full colonoscopy incurs the risk of perforation in these patients, so an unprepped sigmoidoscopy with minimal air insufflation is sufficient and yields the information required at that moment in time to correctly manage the patient.

The incidence of C. difficile in hospitalized patients with UC is rising dramatically and results in increased length of stay and morbidity and mortality [2]. The diagnosis is challenging because patients with severe UC may not have the usual risk factors of antibiotic exposure or recent hospitalization, pseudomembranes are generally not seen at sigmoidoscopy, and if stool toxin assays are relied upon, multiple stool specimens may be necessary before the infection is confirmed. The use of a polymerase chain reaction test for C. difficile significantly reduces false-negative results [3].

CMV superinfection may occur in severe colitis and should be considered in the patient who is not responding to maximal immunosuppressive therapy. The diagnosis can be confirmed with sigmoidoscopic biopsy and viral culture; treatment with ganciclovir may lead to clinical improvement. Evidence of CMV disease can be found in 30 % of cases of severe colitis and its exact role continues to be debated [4]. However, in the patient with fulminant colitis with continuing deterioration, colectomy should not be deferred while awaiting a possible response to treatment for CMV infection.

A plain abdominal film should be performed on admission. Not only will this detect a megacolon but also more subtle radiographic findings of increased small intestinal gas, which predicts a greater likelihood of failure of medical therapy [5]. Any complaints of increasing abdominal pain or distention, especially in a febrile patient, should prompt a CT scan of the abdomen and pelvis to detect subtle signs of colonic perforation, which may be first seen as air within the wall of the colon. The presence of these findings should be followed by emergent subtotal colectomy. In general, medications with anticholinergic or narcotic properties should be avoided because of the theoretical risk of reducing bowel tone and worsening colonic dilatation.

Corticosteroids

IV corticosteroids have been the mainstay of treatment for acute severe colitis for over 50 years [1]. Patients are treated with IV hydrocortisone 100 mg three times daily or an equivalent dose of an alternative IV corticosteroid. There is no benefit to treatment with a higher daily dose of corticosteroids, which exposes the patient to a higher risk of side effects without increased rate of success. There is no benefit to continuous IV corticosteroid infusion compared to bolus dosing three times daily. Historically, almost half of patients with severe colitis did not respond to high-dose IV corticosteroids and required colectomy [6]. The colectomy rate for severe UC has remained consistent over the last 40 years [7].

More recently, it has been recognized that by day 3 of IV corticosteroids, there is a high rate of colectomy in those patients with continued bleeding and greater than six bowel movements daily, elevated CRP, or fevers [8, 9]. These patients, as well as patients who are not decisively improved by days 5–7, should be offered IV cyclosporine, infliximab, or surgery.

Cyclosporine

IV cyclosporine is effective therapy in severe colitis. Multiple series have replicated the 80 % immediate response rate in hospitalized patients failing IV corticosteroids first demonstrated by Lichtiger et al. [10]. Van Assche and colleagues found no difference in efficacy when they compared IV cyclosporine 2–4 mg/kg [11]. It is thought that cyclosporine levels of approximately 200–400 μg/ml are therapeutic during the IV phase. The median time to response is 4 days [12], and predictive factors for failure to respond to cyclosporine include persistent fevers, tachycardia, elevated CRP, hypoalbuminemia, and deep colonic ulcerations [13].

Cyclosporine should only be used by clinicians experienced with its use and who have access to drug level monitoring. Contraindications to its use include active infection, uncontrolled hypertension, renal impairment, and unreliable patients since frequent physician visits are required following discharge from hospital. More common but less severe side effects include paresthesias, hypertension, hypertrichosis, headache, abnormal liver function tests, hyperkalemia, and gingival hyperplasia [14]. Renal function must be monitored closely and serum cholesterol and magnesium should be checked. Low levels of either increase the risk of neurotoxicity, including seizures. Patients with low levels of cholesterol (cholesterol < 120 mg/dl or 3 mmol/l) should be started on lower doses of cyclosporine (or avoid cyclosporine and use infliximab instead, see below), and cholesterol and cyclosporine levels should be monitored daily.

During intervals of triple immunosuppression with corticosteroids, cyclosporine, and thiopurine, we give patients prophylaxis against Pneumocystis jiroveci (carinii) with trimethoprim/sulfamethoxazole 960 mg daily. Serious infections during the IV cyclosporine phase may be due to the concomitant use of corticosteroids rather than the serum level of cyclosporine.

For transitioning to oral cyclosporine before hospital discharge, the IV dose the patient was receiving at the end of the IV phase is doubled and is given in two divided doses daily and generally aiming for trough oral cyclosporine levels of 100–250 μg/ml. In addition, treatment with a thiopurine (6-mercaptopurine or azathioprine) is continued or initiated, and the patient is started on a weekly corticosteroid taper. Failure to taper the prednisone and cyclosporine by 3–6 months is considered a failure. Patients who have already been treated unsuccessfully with an adequate course of a thiopurine prior to cyclosporine are less likely to maintain a long-term remission after the discontinuation of cyclosporine.

6-Mercaptopurine/Azathioprine

Multiple open-label series have demonstrated long-term success with initiating thiopurine therapy during the oral cyclosporine phase in those patients not previously exposed to thiopurines. However, the long-term success rate is lower in those patients who have previously failed adequate courses of thiopurine therapy [15, 16]. In the largest series to date, 83 % of 142 patients had an initial response to cyclosporine and avoided colectomy during hospitalization [16]. Of the 118 patients who responded, 41 (35 %) required a future colectomy. The rate of colectomy in those already taking azathioprine compared with those not previously exposed to azathioprine was 59 % vs. 31 %, respectively. Life-table analysis demonstrated that although only 33 % of patients required colectomy at 1 year, 88 % required colectomy at 7 years.

For patients who have a complete remission in response to cyclosporine and then have a relapse months or years later, a second course of IV cyclosporine followed by oral cyclosporine may be a successful strategy. In 32 patients who flared a mean of 24 months after their initial cyclosporine-induced remission, 44 % avoided colectomy at 3 years after the second course of cyclosporine [17]. Predictors of higher rate of colectomy in these patients were hypoalbuminemia and the presence of C. difficile.

Infliximab

There are limited controlled trial data regarding the role of infliximab in patients with severe UC refractory to IV corticosteroids. In one double-blind series, 45 patients who were naïve to infliximab and refractory to IV corticosteroids, with either fulminant colitis at day 3 or severe colitis at days 6–8, were randomized to either a single dose of infliximab 5 mg/kg or placebo [18]. At day 90, 29 % of infliximab-treated patients with predefined severe colitis had undergone colectomy vs. 67 % of placebo-treated patients. In patients with fulminant colitis, 47 % of infliximab-treated patients underwent colectomy, compared to 69 % of placebo-treated patients. Long-term follow-up of these patients suggested a continued benefit from a single infusion of infliximab even after 3 years [19] with lower colectomy rates in infliximab compared to placebo-treated patients (50 % and 76 %, respectively). However, most of the benefit of infliximab occurred in the first 3 months. In fact, five patients in the infliximab group required colectomy during the long-term follow-up period (i.e., after 3 months and before 3 years) compared to only two in the placebo group. It is possible that a single dose of infliximab may have simply delayed colectomy in the treated patients, leading to more infliximab-treated patients requiring colectomy later on. However, infliximab is rarely given as a single infusion, more commonly being given as three induction doses at 0, 2, and 6 weeks. A retrospective series of severe colitic patients treated with infliximab reported a 50 % colectomy rate at 5 years [20]. Forty percent of patients in this series had more than one infusion. The true long-term benefit of infliximab is unknown, and we think that any strategy involving infliximab will require maintenance infliximab treatment and/or thiopurine therapy.

Infliximab or Cyclosporine as Rescue Therapy?

As discussed above, patients who have previously been intolerant of, or failed to respond to, thiopurine therapy should be offered infliximab preferentially since a large part of the cyclosporine strategy relies on transitioning to thiopurine so that cyclosporine can be stopped after 3–6 months. In contrast, infliximab can be continued as maintenance therapy in those patients who respond to it.

An open-label clinical (CYSIF) trial comparing cyclosporine with infliximab in corticosteroid-refractory severe UC found similar response rates and similar adverse event rates among 115 trial participants [21]. Treatment failure occurred in 60 % patients given cyclosporine and 54 % given infliximab (p = 0.52), while 16 % of patients in the cyclosporine group and 25 % in the infliximab group had severe adverse events. There are no trial data to support the use of other anti-TNF agents (adalimumab and golimumab) in corticosteroid-refractory severe UC.

Immediate and Delayed Sequential Use of Cyclosporine and Infliximab

The immediate sequential use of one of these drugs in the event of failure of the first drug has been studied. A series reported findings among 19 patients who were treated with cyclosporine followed by infliximab (ten patients) or infliximab followed by cyclosporine (nine patients), with either agent being used within 30 days of the other [22]. The 1-year remission rates were low in both groups at 40 % and 33 %, respectively. Serious adverse events occurred in three patients (16 %), including one death due to septicemia. A Spanish group reported their experience among 47 patients treated with infliximab within 1 month of discontinuation of cyclosporine [23]. They reported an immediate colectomy rate of 30 % among this group of patients and one death from sepsis. The French GETAID group reported a colectomy-free survival of 61 % at 3 months and 41 % at 12 months among 86 patients [24]. There was wide variation in timing of the second drug after failure of the first (range 7–163 days). One death and nine infectious complications were reported. It may therefore be inadvisable to use cyclosporine and infliximab or vice versa within 1 month of each other given the limited long-term success and the potential for serious toxicity.

Delayed sequential use of infliximab (at least 1 month after discontinuation of the other drug) appears to be a more acceptable strategy. In a small series among 11 patients, a corticosteroid-free remission occurred in over 64 % of these patients at 1 year and without any serious adverse events when these two drugs were used in this fashion [25]. Delayed use of cyclosporine after infliximab failure, on the other hand, only resulted in 25 % (two of eight patients) of patients achieving a steroid-free remission.

Aminosalicylates

There are no studies to demonstrate that oral aminosalicylates are of clinical benefit in severe colitis, so we have a low threshold for stopping them if the patient has difficulty taking them, but they may be continued if the patient is eating and can tolerate them. Likewise, no controlled studies have confirmed any incremental benefit of rectal medications in this setting, but we still often prescribe them if they can be retained and tolerated, as they help the symptoms of urgency and incontinence, which many patients find distressing.

Antibiotics

In the absence of any proven infection, controlled trials of antibiotics have demonstrated no therapeutic benefit from the use of oral vancomycin, intravenous metronidazole, or ciprofloxacin when added to IV corticosteroids. However, protocols outlining treatment regimens for severe colitis generally include broad-spectrum antibiotics for patients with signs of toxicity or with worsening symptoms despite maximal medical therapy [26]. Antibiotics should be initiated (with coverage for gram negative and anaerobic enteric infections) in the presence of fever or other signs of toxicity, but these may be stopped after 48 h if negative blood and stool culture results return.

Parenteral Nutrition

Controlled studies showed no benefit from total parenteral nutrition (TPN) as a primary therapy for UC [27]. There is no evidence that maintaining oral nutrition is harmful, and it should be continued in patients who can tolerate it, with the exception of patients with colonic dilatation. However, TPN may be useful as a nutritional adjunct in patients with significant nutritional depletion. Those patients with limited expectations of restoring adequate nutritional status and especially in those patients who have a high likelihood of failure of medical therapy and requiring imminent surgery are started on TPN early in their hospital course.

Venous Thromboembolism

This potentially lethal complication occurs approximately twice as frequently in hospitalized UC patients compared to hospitalized controls [28]. For this reason, prophylactic subcutaneous heparin is mandatory for all patients with severe colitis, and the presence of frequent rectal bleeding should not dissuade the clinician of this. Thrombotic events may occur in atypical locations, e.g., portal veins, upper extremities, at sites of IV cannulae, the central nervous system, and in both arterial and venous circulations. For the patient with a series of thrombotic or embolic events during a course of severe colitis, emergent colectomy may be potentially life-saving in preventing additional, potentially fatal thrombi.

Fulminant Colitis and Toxic Megacolon

Patients with fulminant colitis or toxic megacolon should be treated as above; in addition they should be kept NPO, a nasogastric tube or small bowel decompression tube should be considered if a small bowel ileus is present, particularly in patients with vomiting, and the patients should be instructed to rotate frequently into the prone or knee-elbow [29] position to aid in evacuation of bowel gas. A baseline CT should be obtained and followed with daily abdominal x-rays. Broad-spectrum antibiotics are generally used empirically in these patients. The duration of medical treatment of megacolon is controversial; some experts advocate surgery within 72 h if no significant improvement is noted [30], while we may take a more watchful stance if no toxic symptoms are present. However, if there are any clinical, laboratory, or radiologic deterioration on medical therapy, we proceed to emergent subtotal colectomy.

Surgery

Absolute indications for surgery are exsanguinating hemorrhage and frank or suspected perforation. Perforation occurs in 2–3 % of hospitalized UC patients at tertiary referral centers. It is essential to recognize that perforation can occur without being preceded by megacolon and that the initial signs can be masked by corticosteroid use. The surgical procedure of choice is a subtotal colectomy with either a rectosigmoid mucous fistula or Hartmann’s closure. In experienced hands, a laparoscopic approach is not contraindicated if this can be carried out in an expedient fashion.

Patients should be informed of the various future operations available, i.e., total proctocolectomy with permanent ileostomy vs. the ileal pouch-anal anastomosis (IPAA) procedure. IPAA has become the most commonly performed operation for UC and is performed in 1, 2, or 3 stages, but in the patient undergoing urgent colectomy for acute severe colitis, the construction of the ileoanal pouch should always be deferred to a future date, when the patient has been tapered from corticosteroids and has been restored to good health.